The applicant is interested understanding the molecular and cellular mechanisms that govern growth regulation, pattern formation and cell fate choice in the mammalian brain. His focus is on the roles played by intercellular signaling molecules, particularly members of the Wnt gene family. In his previous work, he demonstrated that Wnt-1 is essential for midbrain and anterior hindbrain development since both areas are missing in Wnt-1 mutants. Various studies indicate that Wnt-1 acts in the midbrain, and that the midbrain is required for development of the anterior hindbrain. The working model is that the brain develops as a series of segmental units, each with its own genetic program, but that interactions between adjacent segmental domains are also necessary to coordinate the development of each region. The applicant proposes the following: (1) to further explore the Wnt-1 signaling pathway by examining mutants in porcupine, an endoplasmic reticulum protein which is thought to facilitate Wnt-1 signaling, and to examine the possible later roles of Wnt-1 in the ventral midbrain; (2) to address the action of FGF8, an anterior hindbrain derived signal in reciprocal interactions with the midbrain; and (3) since the restricted expression of other members of the Wnt-family to specific areas of the embryonic brain supports a more extensive role for Wnt-signaling in brain development he proposes to examine strains of mice which lack these factors to unravel the function of these other Wnt-signals in the regulation of forebrain and hindbrain organization.
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